Perturbation of Maleylacetoacetic Acid Metabolism in Rats with Dichloroacetic Acid-Induced Glutathione Transferase Zeta Deficiency

Lantum, Hoffman B M; Cornejo, Judith; Pierce, Robert H.; Anders, M. W.

doi:10.1093/toxsci/kfg104

Cited by 24 publications

(24 citation statements)

References 39 publications

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“…Maleylacetoacetate, the substrate for GSTZ1-1, and its metabolite maleylacetone are electrophiles and can potentially alkylate a range of macromolecules. Their formation and accumulation may play a role in the toxicities associated with GSTZ1 deficiency (Lantum et al, 2003). Thus, the constitutive accumulation of maleylacetoacetate or maleylacetone could also be responsible for the alkylation of Keap1 and the subsequent Nrf2-mediated up-regulation of genes with ARE sequences.…”

Section: Discussionmentioning

confidence: 99%

“…An infant with symptoms consistent with MAAI deficiency died and was never fully characterized (Berger et al, 1988). Dichloroacetic acid is a mechanism-based inhibitor of GSTZ1-1, and treatment of rats with dichloroacetic acid causes a transient partial deficiency of activity that leads to the accumulation of maleylacetoacetate and maleylacetoacetone (Tzeng et al, 2000;Lantum et al, 2003). The therapeutic use of dichloroacetic acid for the treatment of lactic acidosis is also likely to cause a partial deficiency of GSTZ1-1/MAAI but seems to be well tolerated (Stacpoole et al, 1998).…”

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confidence: 99%

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Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways

Blackburn¹,

Matthaei²,

Lim³

et al. 2005

Mol Pharmacol

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Glutathione S-transferase (GST) zeta (GSTZ1-1) plays a significant role in the catabolism of phenylalanine and tyrosine, and a deficiency of GSTZ1-1 results in the accumulation of maleylacetoacetate and its derivatives maleylacetone (MA) and succinylacetone. Induction of GST subunits was detected in the liver of Gstz1 Ϫ/Ϫ mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins. The greatest induction was observed in members of the mu class. Induction of NAD(P)H:quinone oxidoreductase 1 and the catalytic and modifier subunits of glutamate-cysteine ligase was also observed.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways

Blackburn¹,

Matthaei²,

Lim³

et al. 2005

Mol Pharmacol

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“…These are the physiologically important substrates for GSTz1, and both are electrophilic molecules. MA inhibits hepatic GSTz in vitro in a dose-dependent manner (Cornett et al, 1999) that is only partly reversible following removal of MA by dialysis Lantum et al, 2003). The present study was not designed to resolve the mechanism by which GSTz1 is lost from the liver following DCA administration but, rather, to explore the lowest exposure levels associated with this loss.…”

Section: Gstz Enzyme Activity and Protein Expression In Control Ratsmentioning

confidence: 99%

INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONES-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL

Xu¹,

Dixit²,

Liu³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Dichloroacetate (DCA) is an investigational drug for certain metabolic disorders, a by-product of water chlorination and a metabolite of certain industrial solvents and drugs. DCA is biotransformed to glyoxylate by glutathione S-transferase zeta (GSTz1-1), which is identical to maleylacetoacetate isomerase, an enzyme of tyrosine catabolism. Clinically relevant doses of DCA (mg/kg/day) decrease the activity and expression of GSTz1-1, which alters tyrosine metabolism and may cause hepatic and neurological toxicity. The effect of environmental DCA doses (g/kg/day) on tyrosine metabolism and GSTz1-1 is unknown, as is the time course of recovery from perturbation following subchronic DCA administration. Male Sprague-Dawley rats (200 g) were exposed to 0 g, 2.5 g, 250 g, or 50 mg DCA/kg/day in drinking water for up to 12 weeks. Recovery was followed after the 8-week exposure. GSTz specific activity and protein expression (Western immunoblotting) were decreased in a dose-dependent manner by 12 weeks of exposure. Enzyme activity and expression decreased 95% after a 1-week administration of high-dose DCA. Eight weeks after cessation of high-dose DCA, GSTz activity had returned to control levels. At the 2.5 or 250 g/kg/day doses, enzyme activity also decreased after 8 weeks' exposure and returned to control levels 1 week after DCA was withdrawn. Urinary excretion of the tyrosine catabolite maleylacetone increased from undetectable amounts in control rats to 60 to 75 g/kg/24 h in animals exposed to 50 mg/kg/day DCA. The liver/body weight ratio increased in the high-dose group after 8 weeks of DCA. These studies demonstrate that short-term administration of DCA inhibits rat liver GSTz across the wide concentration range to which humans are exposed.

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“…Inside the cell, DCA can be dechlorinated to glyoxylate by glutathione S-transferase ζ1 (GSTZ1) the only enzyme known to metabolize DCA (Lantum et al 2003;Li, WJ et al 2011). GSTZ1 belongs to the cytosolic GST superfamily and is present in cytosol and mitochondria.…”

Section: Dichloroacetate Indirectly Increases Pdc Activitymentioning

confidence: 99%

“…Since DCA can be degraded into glyoxylate by glutathione S-transferase ζ1 (Lantum et al 2003;Li, WJ et al 2011), the stability of DCA in HEK293F cell culture was analyzed first lower in 10 mM DCA cultures. Similarly, the lactate production rate was lower in DCA cultures, about 27% in 5 mM DCA cultures and about 43% in 10 mM DCA cultures.…”

Section: Dca Affects Cell Growth Lactate Production and Pdc Phosphormentioning

confidence: 99%

Global metabolic effect of manipulating pyruvate dehydrogenase complex activity in mammalian cells

Buchsteiner¹

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Aerobic glycolysis is an inefficient metabolic phenotype displayed by many rapidly proliferating cells during growth. It is characterized by high glycolytic activity and only partial oxidation of glucose resulting in the production of high amounts of lactate. This phenotype was originally reported by Otto Warburg in 1927 as a hallmark of cancer andwhile it is now known to occur in other fast growing cells as well -it remains an interesting target for cancer therapy. Aerobic glycolysis also has major implications for biopharmaceutical production, since lactate accumulation can be growth inhibiting, limiting the cell density that can be achieved in culture.Due to its association with various diseases and being an unfavorable metabolic phenotype in industrial applications, reducing the Warburg effect and analyzing accompanying effects on the cell as a whole are of great interest. Whereas in cancer therapy the objective is to kill cells relying on aerobic glycolysis, the aim in industrial applications is to reduce aerobic glycolysis without inducing cell death or inhibiting cell growth. Pyruvate dehydrogenase complex (PDC) is a mitochondrial gatekeeping enzyme determining how much pyruvate is converted to acetyl-CoA and subsequently enters the TCA cycle. PDC activity is regulated by reversible phosphorylation catalyzed by pyruvate dehydrogenase kinase (PDK) (phosphorylation → inactivation) and pyruvate dehydrogenase phosphatase (dephosphorylation → activation). PDC activity can be increased by inhibiting PDK using dichloroacetate (DCA) a known PDK inhibitor, hereby reducing aerobic glycolysis.The objective in this thesis was twofold; i) analyzing metabolic as well as growth inhibitory effects of DCA in human embryonic kidney 293 (HEK293) cells, and ii) investigating the effects of a non growth inhibiting DCA concentration using Chinese hamster ovary (CHO) cells in industrial relevant bioprocesses. In both studies aerobic glycolysis decreased with increasing DCA concentration characterized by reduced glucose consumption and lactate production. At lower DCA concentrations cell growth was unaffected. Furthermore, no increase in oxidative metabolism was detected at low DCA concentration indicating that the cells adopt a more energy efficient metabolism without directing more pyruvate into the TCA cycle. However, it appears that the cytoplasmic pyruvate fraction is reduced as not only less lactate but also less alanine is produced. The metabolic changes observed were mostly attributable to post-translational regulation since transcriptomics and proteomics analyses revealed only minor changes to metabolic enzymes. However, in the absence of iv increased TCA cycle activity, allosteric regulation of glycolytic enzymes did not readily explain reduced glycolysis.Cell growth in HEK293 cells was reduced only at higher DCA concentration when increased cellular stress and TCA cycle activity were detected. Since DCA was found to depolarize mitochondria the increased TCA cycle activity may not result in higher ATP productio...

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Perturbation of Maleylacetoacetic Acid Metabolism in Rats with Dichloroacetic Acid-Induced Glutathione Transferase Zeta Deficiency

Cited by 24 publications

References 39 publications

Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways

Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways

INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONES-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL

Global metabolic effect of manipulating pyruvate dehydrogenase complex activity in mammalian cells

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